Citation or identification of any reference in Section 2 or any other section of this application shall not be construed as an admission that such reference is available as prior art to the present invention.
A classical inflammatory response is characterized by the invasion of monocyte cells into the afflicted tissue within hours after injury. Among these early invaders are macrophages capable of mediating a myriad of functions, from removal of debris and dead cells and dying tissue by phagocytosis to secretion of enzymes and growth factors that facilitate tissue regeneration. Macrophage-derived cytokines, such as platelet-derived growth factor (PDGF), tumor necrosis factor alpha (TNF.alpha.), transforming growth factor beta (TGF.beta.1), heparin-binding epidermal growth factor (HB-EGF), interleukin-1 (IL-1) and interleukin-6 (IL-6), have been shown to have secondary effects on other bone marrow derived cells and on resident cells in the injured tissue.
Several factors are known which modulate macrophage activity. For example, tuftsin, a derivative of IgG, is a potent macrophage stimulator. Interferon-.gamma. and Tumor Necrosis Factor are also potent stimulators. There are also factors which inhibit macrophage activity, called MIFs. For example, a tripeptide, Thr-Lys-Pro, TKP, a synthetic derivative of tuftsin, has been shown to inhibit macrophage migration and reduce secretion of IL-1 macrophages (see Nishioka et al., 1973, Biochem. Biophys. Acta 310:217-228; Bump et al., 1990, Mol. Cell, Biochem. 92:77-84; Fridkin et al., 1989, Crit. Rev. Biochem. Mol. Bio. 24:1-40; Tzehoval et al., 1978. Proc. Natl. Acad. Sci. USA 75:3400-3404; Thanos et al., 1993, J. Neurosci. 13:455-466; Plata-Salaman, 1989, Brain Behav. Immunol. 3:193-213; Wagle et al., 1989, Biochem. Biophys. Rev. Commun. 159:1147-1153; Sienion et al., 1991, Arch. Immunol. Ther. Exp. 39:605-611; Auriault et al., 1985, Immunopharmac. 7:73-79). Another MIF is Tolrestat, an aldose reductase inhibitor (Calcott et al., 1994, Exp. Neurol. 128:226-232).
Mathur and Kishore, 1980,Indian J. Biochem. Biophys. 17:303-305, demonstrated that i.p. administration of 100 mg/kg of a certain peptide and certain peptide derivatives containing arginine into rats resulted in the lowering of blood sugar levels, i.e., the peptides have hypoglycemic activity. The peptides tested having hypoglycemic activity are Arg-Asn, Arg-Asn-NH.sub.2, Asn-Arg-NH.sub.2, Gln-Arg-OMe, Gln-Arg-NH.sub.2, and Glu-Arg-OMe. The peptide Glu-Arg-NH.sub.2 was also tested but did not significantly lower blood sugar levels.
Mathur et al., 1977, Indian J. Biochem. Biophys. 14:384-385, demonstrated that the following peptide derivatives have antilipolytic activity as measured in an in vitro test assay: Arg-Asn-NH.sub.2, Asn-Arg-NH.sub.2, Gln-Arg-NH.sub.2, Glu-Arg-OMe, and Glu-Arg-NH.sub.2. Arg-Asn and Gln-Arg-OMe were tested but showed no significant antilipolytic activity.